Human interleukin-3 is a pleiotropic cytokine that stimulates the production of hemopoietic cells from multiple lineages including neutrophils, eosinophils, monocytes, megakaryocytes, erythroid cells, basophils and B cells. Recently IL-3 has also been shown to regulate vascular endothelial cell functions; enhancing adhesion molecule expression, neutrophil transmigration and cytokine production. Although some of the effects of IL-3 may be desirable and have prompted its clinical use in bone marrow reconstitution following chemotherapy, it is also apparent that abnormal or excessive production of IL-3 has the potential to lead to disease states. For example, some acute myeloid leukaemias proliferate in response to IL-3, and cells from follicular B cell lymphomas produce and depend on IL-3 for their growth. IL-3 has also been implicated in allergy not only for its ability to stimulate eosinophil and basophil production but also for being a strong stimulus of histamine release from basophils in vitro. The detection of elevated amounts of IL-3 mRNA in the skin and bronchi of allergic individuals further suggests an in vivo role in allergy.
The biological activities of human IL-3 are initiated by the binding of IL-3 to its receptor. This consists of two subunits; an .alpha. chain (IL-3R.alpha.) which binds IL-3 specifically and with low affinity,.sup.16 and a .beta. chain (.beta..sub.c) which does not bind ligand on its own but confers high affinity binding when co-expressed with IL-3R.alpha...sup.17,18 Both chains are required for signalling,.sup.18 however, receptor activation and cellular signalling are dependent on IL-3 binding to IL-3R.alpha. as the initial step. The subsequent events are not fully understood but probably involve receptor dimerization leading to the activation of specific kinases associated with the receptor..sup.19,43
The structure of the extracellular domain of human IL-3R.alpha. has not yet been elucidated. Since IL-3R.alpha. belongs to the cytokine receptor family, it is predicted to contain a cytokine receptor module (CRM) with two discrete folding domains..sup.20 In addition there is also an N-terminal domain which, interestingly, has sequence similarities with the human GM-CSF and IL-5 receptor .alpha. chains..sup.21 This feature distinguishes these receptors from the other members of the cytokine receptor family. The functions of the CRM and N-terminal domain of the IL-3R.alpha. chain are not known, nor is it known where the IL-3 binding regions lie in the receptor.